News from Annals of Internal Medicine

mRNA Vaccines Highly Effective at Preventing Death from Covid-19, Less Effective at Preventing Infection

A target trial emulation study found that in an elderly population of U.S. veterans with high comorbidity burden, mRNA vaccine efficacy at preventing infection with COVID-19 was substantially lower than previously reported but effectiveness against death was very high. These finding suggest that complementary infection mitigation efforts remain important for pandemic control, even with vaccination. The study is published in Annals of Internal Medicine.

The real-world effectiveness of the Moderna or Pfizer-BioNTech COVID-19 mRNA vaccines in ethnically and racially diverse populations across the entire United States is not well characterized, especially in more vulnerable populations, such as elderly persons with high comorbidity burden. The U.S. Department of Veterans Affairs (VA) health care system is the largest national, comprehensive health care system in the United States. As such, it offers the opportunity to evaluate vaccines in this population.

Researchers from Veterans Affairs Puget Sound Health Care System and University of Washington School of Medicine designed an observational study to emulate a target trial of COVID-19 vaccination versus placebo. Of the more than 5 million people receiving care in the Veterans Affairs health care system, those who received at least 1 dose of the Moderna or Pfizer–BioNTech COVID-19 vaccine from 11 December 2020 to 25 March 2021 (n = 2,099,871) were matched to unvaccinated controls in a 1:1 ratio according to demographic, clinical, and geographic characteristics. The researchers found that vaccine effectiveness at 7 or more days after the second vaccine dose was 69% for SARS-CoV-2 infection and 86% for SARS-CoV-2–related death during follow-up extending to 30 June 2021. Vaccine effectiveness did not decline when follow-up was extended from 31 March to 30 June 2021. Vaccine effectiveness against SARS-CoV-2 infection decreased with increasing age and comorbidity burden. According to the researchers, these findings suggest that protection against infection from COVID-19, even among vaccinated individuals, will require continued attention to additional mitigation strategies.

Bamlanivimab May Be Effective for Hospitalized Patients with Early SARS-CoV-2 and No Detectable Levels of Endogenous Neutralizing Antibody

A randomized controlled trial found that the neutralizing monoclonal antibody therapy Bamlanivimab may be effective for hospitalized patients with SARS-CoV-2 and no detectable levels of endogenous neutralizing antibody (nAb) at the time of administration. Conversely the therapy may be harmful in patients who have already mounted a nAb response. As such, it is critical to rapidly determine endogenous antibody status in hospitalized patients before administrating neutralizing monoclonal antibody products. The findings are published in Annals of Internal Medicine.

The ACTIV-3/TICO (Accelerating COVID-19 Therapeutic Interventions and Vaccines, Inpatient Monoclonal Antibodies and Other Therapies/Therapeutics for Inpatients With COVID-19) master protocol was set up in June and July 2020 to study the clinical effect and safety of novel antiviral agents against SARS-CoV-2 in patients admitted to hospital with COVID-19 within 12 days of symptom onset compared with placebo. To date, 6 novel investigational agents have been studied. The study of Bamlanivimab in ACTIV-3/TICO was stopped due to futility, meaning there was no evidence of clinical effect.

In the Bamlanivimab substudy of ACTIV-3/TICO 314 patients with SARS-CoV-2 were randomly assigned to receive either Bamlanivimab or placebo.  The patients were followed for 90 days to determine response. At start of the trial, blood was collected from study participants and tested for the presence of endogenous nAb (i.e. the immune response that enables the host from eventually clearing the infection), and markers of ongoing viral replication (including a novel test for viral antigen levels in plasma) to evaluate the prespecified hypothesis that Bamlanivimab has greater benefit in patients without nAb at study entry than in those with antibodies, especially if viral levels are high. The researchers found that Bamlanivimab was clinically effective among those patients that had yet to mount an endogenous nAb response. Such patients typically have uncontrolled viral replication. As such, this finding supported the predetermined hypothesis. Bamlanivimab did not appear to be clinically effective in hospitalised patients that had already mounted an endogenous nAb response. In fact, the administration of exogenous monoclonal antibodies in these patients may actually cause net clinical harm and should be avoided, the researchers say. The mechanism for explaining the harm in these patients remains unclear, but is under active investigation within the ACTIV-3/TICO platform.

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